Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF3S5E3)

• DOT Name: G-protein coupled receptor family C group 5 member B (GPRC5B)
• Synonyms: A-69G12.1; Retinoic acid-induced gene 2 protein; RAIG-2
• Gene Name: GPRC5B
• Related Disease:
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Megalencephalic leukoencephalopathy with subcortical cysts 1
  Non-insulin dependent diabetes
  Diabetic kidney disease
  Lupus nephritis
  Nephropathy
  Megalencephalic leukoencephalopathy with subcortical cysts 3
  Obesity
• UniProt ID: GPC5B_HUMAN
• Pfam ID: PF00003
• Sequence:
  MFVASERKMRAHQVLTFLLLFVITSVASENASTSRGCGLDLLPQYVSLCDLDAIWGIVVE
  AVAGAGALITLLLMLILLVRLPFIKEKEKKSPVGLHFLFLLGTLGLFGLTFAFIIQEDET
  ICSVRRFLWGVLFALCFSCLLSQAWRVRRLVRHGTGPAGWQLVGLALCLMLVQVIIAVEW
  LVLTVLRDTRPACAYEPMDFVMALIYDMVLLVVTLGLALFTLCGKFKRWKLNGAFLLITA
  FLSVLIWVAWMTMYLFGNVKLQQGDAWNDPTLAITLAASGWVFVIFHAIPEIHCTLLPAL
  QENTPNYFDTSQPRMRETAFEEDVQLPRAYMENKAFSMDEHNAALRTAGFPNGSLGKRPS
  GSLGKRPSAPFRSNVYQPTEMAVVLNGGTIPTAPPSHTGRHLW
• Function: G-protein coupled receptor involved in the regulation of cell volume.
• Tissue Specificity: Expression is high in kidney, pancreas, and testis, medium in brain, heart, prostate, small intestine, and spleen, low in liver, placenta, skeletal muscle, colon, ovary, and thymus, and not detectable in lung and peripheral leukocyte. According to PubMed:10945465, highly expressed in most brain areas examined, with the highest levels observed in corpus callosum, caudate nucleus, putamen, substantia nigra, thalamus, hippocampus, and spinal cord as well as in dorsal root ganglia (DRG). Expressed in glia limitans, ependymal cells, astrocyte cell bodies, the perivascular region in astrocyte endfeet, but not in neurons . In the periphery, expression levels are relatively low, compared to the CNS, with the strongest expression detected in pancreas, testis, uterus, and stomach.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[2]
Megalencephalic leukoencephalopathy with subcortical cysts 1	DIS9VTJD	Strong	Autosomal dominant	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[4]
Diabetic kidney disease	DISJMWEY	moderate	Altered Expression	[5]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[5]
Nephropathy	DISXWP4P	moderate	Altered Expression	[5]
Megalencephalic leukoencephalopathy with subcortical cysts 3	DIS5GEYM	Limited	Autosomal dominant	[6]
Obesity	DIS47Y1K	Limited	Genetic Variation	[1]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of G-protein coupled receptor family C group 5 member B (GPRC5B).	[21]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G-protein coupled receptor family C group 5 member B (GPRC5B).	[16]

References

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• [2] Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder.Am J Med Genet B Neuropsychiatr Genet. 2013 Jun;162B(4):295-305. doi: 10.1002/ajmg.b.32144. Epub 2013 Mar 26.
• [3] Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema. Brain. 2023 Aug 1;146(8):3444-3454. doi: 10.1093/brain/awad146.
• [4] GPRC5B a putative glutamate-receptor candidate is negative modulator of insulin secretion.Biochem Biophys Res Commun. 2013 Nov 22;441(3):643-8.
• [5] GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-B Pathway.J Am Soc Nephrol. 2019 Sep;30(9):1573-1586. doi: 10.1681/ASN.2019010089. Epub 2019 Jul 8.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [14] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.